+

WO1997014420A1 - Traitement de la fibrose dans les tissus de muscles squelettiques - Google Patents

Traitement de la fibrose dans les tissus de muscles squelettiques Download PDF

Info

Publication number
WO1997014420A1
WO1997014420A1 PCT/US1996/015888 US9615888W WO9714420A1 WO 1997014420 A1 WO1997014420 A1 WO 1997014420A1 US 9615888 W US9615888 W US 9615888W WO 9714420 A1 WO9714420 A1 WO 9714420A1
Authority
WO
WIPO (PCT)
Prior art keywords
skeletal muscle
group
fibrosis
arginate
metalloporphyrin
Prior art date
Application number
PCT/US1996/015888
Other languages
English (en)
Original Assignee
The Nemours Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Nemours Foundation filed Critical The Nemours Foundation
Priority to AU72547/96A priority Critical patent/AU7254796A/en
Publication of WO1997014420A1 publication Critical patent/WO1997014420A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a method of treating skeletal muscle disease. More specifically, the invention provides a method of reducing skeletal muscle fibrosis by administering a therapeutic amount of a metalloporphynn compound.
  • Skeletal muscle fibrosis is a phenomenon which frequently occurs in diseased or damaged muscle. It is characterized by the excessive growth of fibrous tissue which usually results from the body's attempt to recover from injury. Fibrosis impairs muscle function and causes weakness. The amount of muscle function loss generally increases with the extent of fibrosis. Often fibrosis is progressive and can contribute to the patient's inability to carry out ordinary tasks of independent living, such as grasping objects or walking. Victims of muscular dystrophies, particularly
  • BMD Becker muscular dystrophy
  • DMD Duchenne muscular dystrophy
  • BMD patients usually exhibit progressive muscle weakness and wasting. The advance of fibrosis often causes ever greater loss of mobility and a reduced life expectancy. At some point, the patient may become too weak to walk and takes to a wheelchair. Victims of DMD typically lose the ability to walk by their early teen years and experience tragically premature death before the age of twenty. DMD patients typically succumb to cardio-pulmonary complications which may be partly attributable to strain associated with fibrosis-induced muscle function loss and weakness .
  • Denervation atrophy is a degradation of muscle tissue caused by loss of neural contact to a muscle. The lost neural contact can be due to trauma, for example by accidentally severing a nerve. Neuromuscular disease can produce a similar effect. For example, acute polyneuritis, poliomyelitis, erdig/Hoff an disease, amyotrophic lateral sclerosis, also known as Lou Gehrig's Disease, and progressive bulbar atrophy disease, are known to cause denervation atrophy. Generally, denervated muscle fibers progressively degrade at a rate such that about 75% muscle mass reduction and about 10% muscle volume reduction occur within 120 days of the denervating event.
  • a method of treating skeletal muscle fibrosis in mammals comprising the steps of identifying an individual suspected of suffering from a disorder which targets skeletal muscle tissue, and administering to such individual an effective amount of pharmaceutical composition that includes metalloporphyrin compound to reduce the rate of skeletal muscle fibrotic tissue growth.
  • the metalloporphyrin compound according to the present invention is an organic radical substituted porphine complexed with a cationic metal atom bonded to a functional moiety.
  • a preferred organic radical substituted porphine is the protoporphyrin radical, C 32 H 32 N 4 (COOH) 2 , occasionally referred to as “protoporphyrin IX” and as “PPIX", having vinyl and methyl groups substituted on the porphine structure.
  • metalloporphyrin compounds include molecules in which an atom or atoms or a group or groups from portions of the protoporphyrin radical are replaced by another atom or atoms or group or groups.
  • the vinyl group can be substituted with an ethyl group.
  • other side chains may be substituted.
  • the methyl group may be substituted with a C, to C 4 alkyl or alkenyl group.
  • the cationic metal atom is a metal selected from among the elements of group VIII of the periodic table, such as iron, nickel, ruthenium, cobalt, palladium, platinum and rhodium. Iron and cobalt are particularly preferred.
  • the functional moiety bonded to the metal atom can be an atom, molecule or molecular group, such as a halogen, an amino acid residue, a lower alkyl group, a hydroxyl group and a lower hydroxylated alkyl group.
  • the functional moiety is chlorine, bromine, iodine, arginine residue (arginate), lysine residue or a hydroxyl group. More preferably, the functional group is chlorine or arginate.
  • protoporphyrin compounds based on protoporphyrin IX include, for example, Co PPIX arginate, Fe PPIX Cl, Ru PPIX Cl , Pt PPIX Cl, and the like.
  • protoporphyrin IX is complexed with either iron or cobalt bonded to either chlorine or arginine residue ligand.
  • Ferric protoporphyrin IX in which chlorine is associated with the iron atom is known generally in the pharmaceutical industry as hemin. Hemin is a non-toxic FDA orphan drug which is normally derived from processed red blood cells.
  • hemin is chloro [7, 12-diethenyl-3, 8, 13, 17- tetramethyl-21H, 23H-porphine-2,18-dipropanoato(2-) -N 21 ,N 22 ,N 23 ,N 24 ]iron. Hemin for administration by injection is commercially available from Abbott Laboratories, Inc.
  • Hematin which is suitable for use according to this invention, is the chemical reaction product of hemin with aqueous sodium carbonate solution.
  • the metalloporphyrin compound in which the Fe atom of protoporphyrin IX is bonded to an arginine residue ligand is occasionally referred to herein as heme arginate.
  • Heme arginate is available commercially from Leiras Oy of Turku, Finland under the tradename Normosang®.
  • Preferred metalloporphyrin compounds based on protoporphyrin IX include hemin, hematin, cobalt protoporphyrin IX Cl, cobalt protoporphyrin IX arginate and heme arginate. Hemin, hematin and heme arginate are more preferred, and hemin and hematin are most preferred.
  • mammals which suffer from a disorder characterized by skeletal muscle fibrosis may be treated by administering to such subjects an amount of metalloporphyrin compound effective to reduce the rate of fibrotic tissue growth.
  • TGF- ⁇ transforming growth factor ⁇
  • metalloporphyrin compound has ability to interrupt the cyclic chain of processes by interfering with the release of growth factors by macrophages which invade damaged skeletal muscle in response to muscle damage. In this way metalloporphyrin compound indirectly inhibits fibroblast proliferation, thereby reducing fibrosis development. Consequently, administration of metalloporphyrin compound should effectively retard and prevent subsequent fibrosis. It is unclear, however, whether metalloporphyrin compound administration will destroy existing fibroblasts.
  • Treatment of skeletal muscle fibrosis comprises the steps of identifying individuals who suffer from disorders which target skeletal muscle tissue, and administering to such individuals an effective amount of pharmaceutical composition that includes metalloporphyrin compound to reduce the rate of skeletal muscle fibrotic tissue growth.
  • disorders which target skeletal muscle tissue means diseases, conditions or other abnormal medical states which normally result in skeletal muscle fibrosis.
  • diseases include, for example, muscular dystrophies, such as Duchenne's muscular dystrophy and Becker's muscular dystrophy, and neuromuscular diseases, such as acute polyneuritis, poliomyelitis, Werdig/Hoffman disease, amyotrophic lateral sclerosis, and progressive bulbar atrophy.
  • Such conditions include, for example, traumatic denervation atrophy.
  • suffering from such disorders is meant that the patient exhibits symptoms of an aforementioned disorder and thus is likely to develop debilitating skeletal muscle fibrosis in the normal course of events, even though signs of fibrosis are not evident at the time of diagnosis.
  • Diagnosis of individuals who suffer from disorders which target skeletal muscle tissue may be readily made by those having ordinary skill in the art using well established criteria and methods.
  • compositions containing metalloporphyrin compound can be formulated for human and animal prophylactic and therapeutic applications by those having ordinary skill in the art.
  • Pharmaceutical formulations for administering hemin for the treatment of porphyrias are well understood. Consequently, it should be possible to formulate pharmaceuticals for administering metalloporphyrin compounds to treat skeletal muscle fibrosis, based on known hemin formulations, without undue experimen ation.
  • metalloporphyrin compound administered to mammals, and particularly to humans, to be effective in treating or preventing skeletal muscle fibrosis can be determined by those having ordinary skill in the art.
  • a methodology for determining appropriate dosage includes determining the existing state of skeletal muscle fibrosis of a patient; administering at a preselected frequency, a preselected amount of pharmaceutical formulation containing metalloporphyrin compound; determining the state of skeletal muscle fibrosis exhibited by the patient at a later time when the disorder, if untreated, would have increased fibrotic tissue development; and applying an adjustment to the dosage amount and/or delivery rate to reduce, maintain or increase the effect of preventing or reducing fibrosis.
  • a number of methods are available to determine the state of skeletal muscle fibrosis of a patient.
  • One such method includes obtaining a biopsy of muscle tissue from the patient, and evaluating the biopsy with histochemical or im uno-histochemical stains sensitive to detect the existence of fibrotic tissue.
  • histochemical stains include, for example, hematoxylin and eosin (H & E), trichrome and ATPase (at pH 4.3, 4.65 and 10.4) .
  • Representative antibodies which can be used to label muscle fibers for immuno-histochemical staining include, for example, myosin, type IV collagen, laminin, fibronectin and dystrophin.
  • a functional method of determining the extent to which fibrosis pervades a patient's skeletal muscle can be employed.
  • the functional method involves subjecting the patient to one or more of a battery of tests and physical measurements.
  • tests and measurements typically include neurological strength tests, muscle strength, balance, gait, posture, sensory coordination evaluations, and pulmonary function tests, e . g. , vital capacity and forced expiratory capacity, all of which can be carried out by methods well known in the art .
  • compositions that include metalloporphyrin compound may be administered by any method that can deliver metalloporphyrin to the site in the body of a mammal where activity is to occur. These methods include but are not limited to oral, subcutaneous, transdermal, intravenous, intramuscular, liposomal and parenteral methods of administration. In order to treat fibrosis confined to a specific site, a site-specific method of delivery is preferred. For example, to treat fibrosis associated with denervation atrophy caused by traumatic injury to one or a group of nerves affecting muscles in a localized region of the body, delivery of metalloporphyrin compound directly to the affected muscles, such as by intramuscular injection, may be used to advantage.
  • Intravenous infusion is a preferred method of delivery whether or not the treatment area is localized.
  • metalloporphyrin compounds are commercially supplied in solution of solvents which are myotoxic.
  • Normosang® is understood to be heme arginate dissolved in propanediol and ethanol. Brazeau, G.A. and Fung, H-L, in Mechanisms Of Crea tine Kinase Release From Isola ted Rat Skeletal Muscles Damaged By Propylene Glycol and Ethanol , Journal of Pharmaceutical Sciences 79, pp.
  • the dosage administered in any particular instance will depend upon factors such as the mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment, and the effect desired. In order to obtain efficacious results, it is desirable to achieve at least about 100 nM concentration of metalloporphyrin compound in the locality of tissue to be protected from fibrosis.
  • the dosage amounts and frequency of administration should be capable of producing local concentrations of about 100-500 nM soon following administration and about 100-200 nM for a sustained period of up to several days after administration.
  • the dosage of metalloporphyrin compound of the invention will be in the range of from about 0.25 mg to about 20 mg per kg of body weight, preferably from about 1 mg to about 12 mg per kg body weight, more preferably from about 1 mg to about 6 mg per kg of body weight, and most preferably 1 mg to about 3 mg per kg of body weight. It is contemplated that these doses of metalloporphyrin compound will be delivered in a single dosage, divided dosages or in a sustained release during a period preferably less than 24 hours, and preferably, about one hour. Some metalloporphyrin compounds, such as hemin, are susceptible to rapid conversion to billirubin and thus are excreted in substantial fraction via the liver.
  • Dosage amount and frequency of administration may need to be increased to compensate for the therapeutic agent which is so purged prior to reaching the target. This need to boost dosage and frequency is primarily of concern for the systemic methods of delivery. Persons of ordinary skill in the art will be able to determine dosage forms and amounts with only routine experimentation based upon the disclosure of this invention as recited herein.
  • the aforementioned dosages will be administered at intervals of about 5 to about 9 days, that is, about weekly.
  • administration should continue until the affected muscle no longer exhibits atrophy and fibrosis as determined by functional tests and/or biopsy evaluation or becomes stabilized.
  • dosage administration should continue on about a weekly frequency for the life of the patient or until the patient's muscular state ceases to show increasing fibrosis development as determined by the above described methods.
  • Hemin, hematin and hemin arginate are preferably administered intravenously in sterile liquid dosage forms. Hemin may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. For example, see Remington 's Pharmaceutical Sciences, 17th ed., A. R. Gennaro, Mack Publishing Company, Easton, Pennsylvania (1985), p. 842, incorporated herein by reference.
  • Panhematin® hemin is sold in single doses as a sterile, lyophilized black powder suitable for intravenous infusion after reconstitution with USP grade sterile water as described in the Physicians Desk Reference® Medical Economics Data Production Co., Montvale, N.J., (1995) pp. 447-448, incorporated herein by reference.
  • individuals are identified for whom prevention or reduced growth rate of skeletal muscle fibrosis development is desired.
  • Skeletal muscle tissue in which fibrosis development has either begun or is likely to occur is biopsied and stained for necrotic muscle tissue and fibrosis.
  • the individuals are functionally tested for muscle strength, balance, gait, posture, sensory coordination and pulmonary capacity.
  • Hematin is administered to such individuals by intravenous infusion in doses which total 1 to 4 mg/kg/day of hematin over a period preferably of about 10 to about 30 minutes, and more preferably of about 10 to about 15 minutes, for a period in the range of 3 to 14 days based on the benchmark clinical results.
  • hematin No more than 6 mg/kg of hematin should be given in any 24-hour period.
  • the individuals are again subjected to functional testing.
  • the process of hematin administration and functional testing is repeated until signs indicate that skeletal muscle fibrosis is stabilized.
  • biopsies are performed to confirm that fibrosis development is under control.
  • the dosage and frequency of hematin administration can be reduced gradually and possibly totally eliminated.
  • heme arginate as supplied by Leiras Oy, for example, is administered to treat skeletal muscle fibrosis. Heme arginate has greater stability relative to hemin. See Tokola, 0., et al . (1986) Br. J. Clin. Pharmac .
  • Heme arginate is formulated and administered in manner similar to hemin. It is preferred that 3 mg/kg patient weight be administered by intravenous infusion as described in Tokola, 0. et ai . , supra .
  • the present invention relates primarily to reducing or preventing debilitating fibrosis in skeletal muscle tissue by administering effective amounts of metalloporphyrin compounds.
  • metalloporphyrin compounds are effective amounts that can be used to treat this disorder.
  • one theory for the success of metalloporphyrin compounds in treating this disorder centers upon belief that metalloporphyrin interferes with growth factors that mediate production of fibrotic skeletal muscle tissue.
  • Growth factors responsible for fibrosis in skeletal muscle tissue may also be involved n fibrotic cell development in non-skeletal muscle and other connective tissue, such as the heart, lungs, the alimentary system and other ma ⁇ or internal organs.
  • the present invention provides treatment of fibrosis by administering pharmaceutical formulations including effective amounts of metalloporphyrin compound to reduce or prevent fibrosis in non-skeletal muscle tissue.
  • pharmaceutical formulations including effective amounts of metalloporphyrin compound to reduce or prevent fibrosis in non-skeletal muscle tissue.
  • the nature of metalloporphyrin compound, the methods of administration and the dosage and frequency of delivery are substantially similar to those disclosed above in connection with the method of treating skeletal muscle fibrosis.
  • Bovine hemin obtained from Calbiochem, San Diego, California, was freshly dissolved in 0. IN NaOH to a 4 mM stock solution, and was filter-sterilized. Heme arginate was synthesized according to the method of Tenhunen, R., Tokola, 0. and Linden, I.-B. Haem Argina te : a New Stable Haem Compound, J. Pharm. Pharmacol. 39, pp 780-786 (1987), which is incorporated by reference herein, as follows. 200.3 g L-arginine was added to 10 g ethanol and 40 g propylene glycol. Deionized water was added to increase total volume to 100 ml.
  • the tibialis anterior muscle of the contralateral leg of each of two of the rats was injected with identical amounts of the muscle-destroying agent to which was added either 5, 10, or 20 ⁇ M bovine hemin (Example 1) or 5, 10, or 20 uM heme arginate (Example 2) .
  • One muscle of each of two control rats was injected with 0.2 ml of 0.9 wt/vol % saline solution and the other muscle was not injected (Comparative Example 1) . Injections were repeated weekly for 20 consecutive weeks.
  • rats Six weeks after final injections, rats were sacrificed by decapitation, the tibialis anterior muscles were rapidly removed, trimmed of fascia and connective tissue, divided in half, and mounted in 10% gum tragacanth on a cork chuck. Each sample was rapidly frozen in isopentane by cooling in liquid nitrogen to about -160°C, then placed with a drop of water in screw cap container and stored at -70°C. Frozen muscle samples were brought to cryostat temperature of about -20°C prior to sectioning. 12 ⁇ m transverse sections were cut on a Bright microtome, placed on microscope slides, and dried in air overnight. Sections were stained with hematoxylin, eosin, Gomori trichrome, acid phosphatase,
  • NADH-tetrazolium reductase periodic acid-Schiff, and after preincubation at pH 4.6 and 4.2, with ATPase at pH 9.4.
  • Example 1 rat died, perhaps from bupivacame entry into the bloodstream. Histological analysis of the bupivacame-in]ected muscle tissue showed areas of necrosis, wider myofiber spacing and extensive macrophage infiltration. The contralateral muscle into which hemin had been injected with bupivacaine, showed more regenerated myofibers, closer spacing and fewer macrophages. Bupivacaine or bup ⁇ vaca ⁇ ne/5 ⁇ M bovine hemin was added to cultures of regenerated myotubes. Cultured skeletal myotubes in both samples were immediately destroyed, which indicated that hemin d d not interfere with the myotoxic ty of bupivacaine.
  • Muscles injected exclusively with bupivacaine showed variation of myofiber size, numerous internal nuclei indicative of muscle regeneration, and per ysial and endo ysial fibrosis. Muscles treated with nemm along with bupivacaine showed more normal and homogenous fiber size and little endomysial fibrosis. Numerous internal nuclei were also observed in the hemin-treated muscles, suggesting that muscle damage and subsequent regeneration had occurred. The greatest effect was observed at the 5 uM level in Example 1.
  • an Alzet® Model 2001 Mini-Osmotic pump from Alza Corporation, Palo Alto, CA was implanted in the subcutaneous space of each of 175-200g, Sprague-Dawley rats.
  • the pump rate was set at 1.0 ⁇ L/h to deliver 2.9 ⁇ g/h hemin (Example 5), 2.9 ⁇ g/h heme arginate (Example 6), 0.1 N NaOH solution, (Comparative Example 4) or 0.23 M ethanol/0.55 M propanediol solution (Comparative Example 5) .
  • bupivacaine was injected into the tibialis anterior muscles of the subjects, as described above. Pumps were replaced weekly during the course of the experiment. Injections were continued on a frequency of three times per week for four consecutive weeks.
  • Muscles from rats that had been exposed to hemin showed muscle cell regeneration, closer myofiber spacing, less myofiber size variability and less fibrosis than those exposed to heme arginate, hemin vehicle or heme arginate vehicle.
  • the results of the above described examples are consistent with the observation, previously mentioned, that the organic solvents present in commercial formulations of heme arginate, namely, ethanol and propanediol, are myotoxic. This explains why the heme arginate treatments by intramuscular injection and all subcutaneously delivered treatments involving heme arginate vehicle yield less satisfactory results than those of hemin treatments.
  • the metalloporphyrin compound was prepared as a 4 mM stock solution in 0.1 N NaOH. The stock solution was added to the proliferation medium to produce a 20 ⁇ M concentration. The metalloporphyrin compound-containing proliferation medium was filtered through a 0.2 ⁇ m filter prior to addition to the flasks. Cell doubling times are reported in Table I.
  • both cobalt protoporphyrin IX chloride and ferric protoporphyrin IX chloride (hemin) appreciably increased fibroblast doubling time in both rat and human models.
  • Both metalloporphyrin compounds extended fibroblast doubling by about 72 % in rat culture and by about 39 % in human culture.
  • Myosin:DNA stain intensity ratios of Co PPIX Cl and Fe PPIX Cl treated cultures were not much different from the control. The data thus show that Co PPIX Cl and Fe PPIX Cl can effectively retard fibrotic tissue development without adversely affecting the ability of human muscle cells to convert to myotubes.
  • Sn PPIX Cl moderately improved the fibroblast cell doubling time in rat culture only. Visual evaluation of confluent cell cultures indicated that Sn PPIX Cl treated cells did differentiate to form myotubes. In view of the modest retardation of human fibroblast doubling, histological myotube development determination was not performed for Example 9. The presence of Cr PPIX Cl significantly retarded fibroblast doubling in humans, however, Zn PPIX Cl, Cr PPIX Cl and Mn PPIX Cl treatment substantially interfered with myotube development as determined by visual inspection. Mn PPIX Cl treatment accelerated human fibroblast growth and Zn PPIX Cl treatment at 20 ⁇ M concentration proved lethal to rat cells after seven days of exposure.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de traitement de la fibrose des muscles squelettiques chez les mammifères. Ce procédé nouveau est efficace pour réduire l'étendue de la fibrose des muscles squelettiques chez un sujet qui souffre d'une affection visant ce tissu, comme la dystrophie musculaire de Duchenne et Becker et l'atrophie par dénervation, causée soit par un traumatisme, soit par une maladie neuromusculaire. Le traitement comprend l'administration d'une quantité efficace d'un composé de métalloporphyrine, spécialement l'hémine, l'arginate d'hème, le chlorure de protoporphyrine IX de cobalt et l'arginate de protoporphyrine IX de cobalt.
PCT/US1996/015888 1995-10-16 1996-10-04 Traitement de la fibrose dans les tissus de muscles squelettiques WO1997014420A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72547/96A AU7254796A (en) 1995-10-16 1996-10-04 Treating fibrosis in skeletal muscle tissue

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/543,812 US5604199A (en) 1994-03-29 1995-10-16 Method of treating fibrosis in skeletal muscle tissue
US08/543,812 1995-10-16

Publications (1)

Publication Number Publication Date
WO1997014420A1 true WO1997014420A1 (fr) 1997-04-24

Family

ID=24169641

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/015888 WO1997014420A1 (fr) 1995-10-16 1996-10-04 Traitement de la fibrose dans les tissus de muscles squelettiques

Country Status (3)

Country Link
US (1) US5604199A (fr)
AU (1) AU7254796A (fr)
WO (1) WO1997014420A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6127356A (en) 1993-10-15 2000-10-03 Duke University Oxidant scavengers
JP2001521939A (ja) 1997-11-03 2001-11-13 デューク・ユニバーシティー 置換されたポルフィリン類
US6117445A (en) * 1998-01-28 2000-09-12 Link Technology Inc. Methods for the prevention and treatment of fibrosis and sclerosis
DK1616869T3 (da) * 1999-01-25 2012-05-07 Nat Jewish Health Substituerede porphyriner og deres terapeutiske anvendelse
US20030069281A1 (en) * 2000-06-14 2003-04-10 Irwin Fridovich Tetrapyrroles
DK1392328T3 (da) * 2001-01-19 2009-11-09 Nat Jewish Health Medikament til beskyttelse i radioterapi
EP1439842A4 (fr) * 2001-06-01 2009-09-02 Nat Jewish Med & Res Center Capteurs oxydants destines au traitement du diabete ou a etre utilises dans une transplantation ou a induire une tolerance immunitaire
EP1513537A4 (fr) * 2002-06-07 2006-09-06 Univ Duke Porphyrines substituees
ES2600469T3 (es) 2008-05-23 2017-02-09 National Jewish Health Un compuesto para su uso en el tratamiento de lesiones asociadas con la exposición al gas fosgeno o al gas de cloro

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4067971A (en) * 1976-05-13 1978-01-10 The Procter & Gamble Company Therapeutic composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4067971A (en) * 1976-05-13 1978-01-10 The Procter & Gamble Company Therapeutic composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS ON STN, Biosis Number 96:235548, EL-ETRI et al., "Metalloporphyrin Chloride Ionophores: Induction of Increased Anion Permeability in Lung Epithelial Cells", June 1996. *

Also Published As

Publication number Publication date
AU7254796A (en) 1997-05-07
US5604199A (en) 1997-02-18

Similar Documents

Publication Publication Date Title
Gristwood et al. Levobupivacaine: a new safer long acting local anaesthetic agent
EP0702551B1 (fr) Compositions et procedes de reparation et de prevention de lesions du type fibrose
EP1054665B1 (fr) Composition pharmaceutique comprenant une combinaison de metformine et de fibrate, et son utilisation pour la preparation de medicaments destines a reduire l'hyperglycemie
JP4097285B2 (ja) 種々の頑固な疾患の治療のための医薬の製造に有用な組成物
KR100638684B1 (ko) 말초 혈관 질환의 치료를 위한 9-데옥시-2',9-알파-메타노-3-옥사-4,5,6-트리노르-3,7-(1',3'-인터페닐렌)-13,14-디하이드로-프로스타글란딘 에프1의 용도
HU217543B (hu) Eljárás perifériás neuropátia kezelésére és megelőzésére alkalmas gyógyászati készítmények előállítására, valamint inzulinszerű növekedési faktor I-et és kemoterápiás szert tartalmazó gyógyászati készítmények
AU8310198A (en) Method of treatment of diabetic neuropathy and vascular change or diabetic retinopathy
CA1333998C (fr) Compositions hypocholesterolemiantes a base de combinaisons de niacine et de sels de magnesium
JP2001518096A (ja) アポトーシス性酵素を不活性化するためのニトロシル化
EP1461033B1 (fr) Methodes et compositions permettant de diminuer les effets indesirables de la chimiotherapie
US5604199A (en) Method of treating fibrosis in skeletal muscle tissue
BG65847B1 (bg) Приложение на производни на бигуанидина за получаване на лекарствено средство с цикатризиращ ефект
WO2001010387A2 (fr) Utilisation de modulateurs de p-glycoproteine dans un traitement antiviral
US6316458B1 (en) Method of enhancing insulin action
JP2010535159A (ja) レオヌリンの使用およびその組成物
US5964224A (en) Method for treating amyotrophic lateral sclerosis and a therapeutic agent therefor
JP3253302B2 (ja) ３−ジアルキルアミノエトキシベンゾイル−ベンゾフランを含有する非経口溶液
DE69733207T2 (de) Verfahren zur hemmung von elf5a-biosynthese
KR20040063943A (ko) 안과 질환 및 질병의 치료를 위한 과산화물 디스뮤타제모방체
JPH08507774A (ja) 手術後の悪心および嘔吐の治療のためのグラニセトロンの使用
US7691864B2 (en) Anti-hypertensive composition and methods of treatment
KR100514009B1 (ko) 1,2,4-벤조트리아진옥사이드제제
KR101059330B1 (ko) 3,７­디아자비시클로〔３,３,１〕노난 화합물을 포함하는 액상의 약제학적 제제 및 부정맥발작에 관련한 치료방법
CN111840512B (zh) 治疗软骨修复和/或骨关节炎的组合物
WO2005079792A1 (fr) Agents préventifs ou thérapeutiques pour la rétinopathie diabétique sévère

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP NZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97515843

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载